Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4<sup>+</sup> T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4<sup>+</sup> T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.

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Publication Details

Journal
Nature Genetics
Published
2025-09-18
DOI
https://doi.org/10.1038/s41588-025-02301-3
Citations
2
Primary Topic
Diabetes and associated disorders
Type
article
Field-Weighted Citation Impact
3.63
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article

Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks

Troy A. McDiarmid, Arpit Mishra, Jane H. Buckner, Carl G. de Boer et al.
2 citations
Nature Genetics
Diabetes and associated disorders
3.63
article

Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks

Troy A. McDiarmid, Arpit Mishra, Jane H. Buckner, Carl G. de Boer, Samantha Hardy, Hannah A. DeBerg, Florence M. Chardon, Harshpreet Chandok, Ching‐Huang Ho, John Ray, Michael H. Guo, Ryan Tewhey, LeAnn P. Nguyen, Jay Shendure, Stephan Pribitzer, Maxwell A. Dippel, Meghan S. McQuade
article en
2 citations

Abstract

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4<sup>+</sup> T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4<sup>+</sup> T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.

Nature GeneticsVol. 57(10)
Howard Hughes Medical Institute (US), University of British Columbia (CA), University of Washington (US), Institute for Systems Biology (US), Institute of Translational Health Sciences (US), Jackson Laboratory (US), Brotman Baty Institute (US), Bioarray Genetics (United States) (US), University of Pennsylvania (US)
Openalex Percentile: Top 7%
Diabetes and associated disorders
3.63
DOIOpen Access PDFOpenAlex
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